The primary mission of the SRA is to understand the basic biological mechanisms, genetic and physiological risk factors, predictive diagnostic biomarkers, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This project will test the principal hypothesis that mutation of single genes co-expressed in brain, heart, and brainstem central autonomic neurons increase SUDEP risk by promoting cardiorespiratory arrhythmias. We will identify and validate novel ictal bradycardia and SUDEP gene candidates in mouse models to expand the SUDEP risk genome, and use modifier genes that suppress this risk in forebrain and brainstem autonomic circuits to genetically dissect critical SUDEP pathways. We will examine molecular excitability mechanisms perturbed by these genes in brain and heart, and the role of seizures and hypoxia in pathological network depolarization. We will also explore translational pharmacologic and genetic rescue strategies in these models. These findings will contribute to future genetic risk profiling for SUDEP in clinical exomes and point to new gene-directed approaches to reduce SUDEP in patients at high risk.

Public Health Relevance

The primary mission of the SUDEP Research Alliance is to increase our understanding of the basic biological mechanisms, genetic and physiological risk factors, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This study will search for genes expressed in the brain and heart that may increase the risk of cardiac arrhythmias. Further investigation of these genes in mouse models will examine the molecular excitability changes in brain circuits that regulate the heart rate and pattern of breathing, and explore pharmacological methods of reversing the defects to reduce the SUDEP risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS090340-01
Application #
8817475
Study Section
Special Emphasis Panel (ZNS1-SRB-B (40))
Program Officer
Fureman, Brandy E
Project Start
2014-09-30
Project End
2019-07-31
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$643,104
Indirect Cost
$213,104
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030